Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition
© 2023 Nguyen, Imanishi, Li, Chau, Banerjee, Velatooru, Ko, Samanthapudi, Lee, Abe, McBeath, Deswal, Lin, Palaskas, Dantzer, Fujiwara, Borchrdt, Turcios, Olmsted-Davis, Kotla, Cooke, Wang, Abe and Le..
Background: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear.
Method: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation.
Result: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS).
Summary: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Frontiers in cardiovascular medicine - 10(2023) vom: 15., Seite 1187490 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nguyen, Minh T H [VerfasserIn] |
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| Links: |
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| Themen: |
Atherosclerosis |
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| Anmerkungen: |
Date Revised 10.10.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3389/fcvm.2023.1187490 |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Nguyen, Minh T H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 10.10.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 Nguyen, Imanishi, Li, Chau, Banerjee, Velatooru, Ko, Samanthapudi, Lee, Abe, McBeath, Deswal, Lin, Palaskas, Dantzer, Fujiwara, Borchrdt, Turcios, Olmsted-Davis, Kotla, Cooke, Wang, Abe and Le. | ||
| 520 | |a Background: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear | ||
| 520 | |a Method: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation | ||
| 520 | |a Result: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS) | ||
| 520 | |a Summary: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CHK1 | |
| 650 | 4 | |a SENP2 | |
| 650 | 4 | |a SUMOylation | |
| 650 | 4 | |a atherosclerosis | |
| 650 | 4 | |a endothelial activation | |
| 650 | 4 | |a fibrotic changes | |
| 650 | 4 | |a laminar flow | |
| 700 | 1 | |a Imanishi, Masaki |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Chau, Khanh |e verfasserin |4 aut | |
| 700 | 1 | |a Banerjee, Priyanka |e verfasserin |4 aut | |
| 700 | 1 | |a Velatooru, Loka Reddy |e verfasserin |4 aut | |
| 700 | 1 | |a Ko, Kyung Ae |e verfasserin |4 aut | |
| 700 | 1 | |a Samanthapudi, Venkata S K |e verfasserin |4 aut | |
| 700 | 1 | |a Gi, Young J |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Ling-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Abe, Rei J |e verfasserin |4 aut | |
| 700 | 1 | |a McBeath, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Deswal, Anita |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Steven H |e verfasserin |4 aut | |
| 700 | 1 | |a Palaskas, Nicolas L |e verfasserin |4 aut | |
| 700 | 1 | |a Dantzer, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Fujiwara, Keigi |e verfasserin |4 aut | |
| 700 | 1 | |a Borchrdt, Mae K |e verfasserin |4 aut | |
| 700 | 1 | |a Turcios, Estefani Berrios |e verfasserin |4 aut | |
| 700 | 1 | |a Olmsted-Davis, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Kotla, Sivareddy |e verfasserin |4 aut | |
| 700 | 1 | |a Cooke, John P |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guangyu |e verfasserin |4 aut | |
| 700 | 1 | |a Abe, Jun-Ichi |e verfasserin |4 aut | |
| 700 | 1 | |a Le, Nhat-Tu |e verfasserin |4 aut | |
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